Atherogenic properties of enzymatically degraded LDL - Selective induction of MCP-1 and cytotoxic effects on human macrophages
Atherogenic properties of enzymatically degraded LDL - Selective induction of MCP-1 and cytotoxic effects on human macrophages
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DOI：
10.1161/01.atv.18.9.1376
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发表时间：
1998-09-01
影响因子：
8.7
通讯作者：
Bhakdi, S
中科院分区：
文献类型：
--
作者：
Klouche, M;Gottschling, S;Bhakdi, S
巨噬细胞在早期动脉粥样硬化病变中选择性积聚的机制尚不清楚，但可能与内皮下沉积的改变的低密度脂蛋白（LDL）的特定性质有关。LDL的酶促非氧化降解将脂蛋白转化为潜在的致动脉粥样硬化部分，酶促改变的LDL（E-LDL），其激活补体并通过清道夫受体依赖性途径被人巨噬细胞快速摄取。免疫组织学证据表明，E-LDL是目前在细胞外的位置在早期病变。我们报告说，E-LDL导致大量的单核细胞趋化蛋白1（MCP-1）从巨噬细胞的释放和白细胞介素8或RANTES的表达保持不变。MCP-1的释放之前，MCP-1 mRNA的快速表达，这是可检测的15分钟后，1小时后达到最高水平，并保持可检测的12小时后，暴露于浓度低至10 μ g/mL的E-LDL。E-LDL对MCP-1 mRNA的诱导和蛋白质的释放均超过氧化LDL。MCP-1的释放依赖于从头蛋白质合成和酪氨酸激酶的活性。在较高浓度下，E-LDL，但不是氧化LDL，对巨噬细胞产生毒性作用，部分似乎是由于细胞凋亡。结果表明，E-LDL具有致动脉粥样硬化脂蛋白的主要特性。
The mechanisms underlying the selective accumulation of macrophages in early atherosclerotic lesions are poorly understood but are likely to be related to specific properties of altered low density lipoprotein (LDL) deposited in the subendothelium. Enzymatic, nonoxidative degradation of LDL converts the lipoprotein to a potentially atherogenic moiety, enzymatically altered LDL (E-LDL), which activates complement and is rapidly taken up by human macrophages via a scavenger receptor-dependent pathway. Immunohistological evidence indicates that E-LDL is present in an extracellular location in the early lesion. We report that E-LDL causes massive release of monocyte chemotactic protein 1 (MCP-1) from macrophages and that expression of interleukin 8 or RANTES remains unchanged. Release of MCP-1 was preceded by a rapid expression of MCP-I mRNA, which was detectable after 15 minutes, reached maximum levels after 1 hour, and remained detectable for 12 hours after exposure to concentrations as low as 10 mu g/mL E-LDL. MCP-1 mRNA induction and protein release by E-LDL exceeded that evoked by oxidized LDL. Release of MCP-1 was dependent on de novo protein synthesis and on the activity of tyrosine kinases. At higher concentrations, E-LDL, but not oxidized LDL, exerted toxic effects on macrophages that in part appeared to be due to apoptosis. The results show that E-LDL possesses major properties of an atherogenic lipoprotein.